Journal Article

DKFZ-2024-01391

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours.

Seiboldt, T. (First author)DKFZ* ; Zeiser, C.DKFZ* ; Nguyen, D.DKFZ* ; Celikyürekli, S.DKFZ* ; Herter, S.DKFZ* ; Najafi, S.DKFZ* ; Stroh-Dege, A.DKFZ* ; Meulenbroeks, C. ; Mack, N.DKFZ* ; Salem-Altintas, R.DKFZ* ; Westermann, F.DKFZ* ; Schlesner, M.DKFZ* ; Milde, T.DKFZ* ; Kool, M.DKFZ* ; Holland-Letz, T.DKFZ* ; Vogler, M.DKFZ* ; Peterziel, H.DKFZ* ; Witt, O.DKFZ* ; Oehme, I. (Last author)DKFZ*

2024
Nature Publ. Group Edinburgh

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Please use a persistent id in citations: doi:10.1038/s41416-024-02740-5

Abstract: Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches.We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected BCL-2 family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing.Group 3 medulloblastoma (MBG3) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MBG3 and BCL2 in neuroblastomas. Co-treatments with RA and BCL-2/XL inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of BIM to BCL-XL in MBG3 and to BCL-2 in neuroblastoma, inducing apoptosis in vitro and in vivo.RA treatment primes MBG3 and NB cells for apoptosis, triggered by navitoclax cotreatment.

Note: #EA:B310#LA:B310# / 2024 Sep;131(4):763-777

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Contributing Institute(s):

1. KKE Pädiatrische Onkologie (B310)
2. DKTK HD zentral (HD01)
3. Core Facility Omics IT (W610)
4. B062 Pädiatrische Neuroonkologie (B062)
5. B087 Neuroblastom Genomik (B087)
6. C060 Biostatistik (C060)
7. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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